ASA: Donepezil (Aricept) Comes Up Short in Vascular Dementia Trials

Action Points

Explain to interested patients that this report describes an unapproved use for a drug that is approved for treatment of Alzheimer's disease.

Note that the study failed to meet its primary endpoint, so any positive findings on secondary endpoints can only be considered hypothesis-generating and do not meet the standard of clinical evidence.

NEW ORLEANS, Feb. 25 -- The Alzheimer's disease drug donepezil (Aricept) does not improve cognition in patients with a genetic form of subcortical ischemic dementia known as CADASIL.

Eighteen weeks of daily donepezil (10 mg) did not improve scores on the vascular AD assessment scale subscale (V-ADAS-cog) compared with placebo, Martin Dichgans, M.D., of Ludwig Maximilians University in Munich, Germany, reported at the American Stroke Association's International Stroke Conference.

The findings of the placebo-controlled trial of 168 patients with CADASIL, or cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy, were simultaneously published online by Lancet Neurology.

"There were improvements in executive function, which was a secondary endpoint, but those improvements were not sufficient to make a clinical recommendation," Dr. Dichgans said.

Donepezil is approved for treatment of mild, moderate, and severe Alzheimer's disease.

CADASIL is a disease of white matter, said Philip Gorelick, M.D., M.P.H., of the University of Illinois at Chicago, "so it seemed intuitive that donepezil might have some benefit."

But based on the results reported by Dr. Dichgans, "it is highly unlikely that this drug will be approved for CADASIL," said Dr. Gorelick, who chaired an ASA press briefing where the trial was discussed.

Data from 161 of the 168 randomized patients were included in the analysis; 84 patients were randomized to donepezil. The mean age of patients in the study was 54.8 years.

"The least-squares mean change from baseline score was -0.81 (SE 0.59) in the placebo group and -0.85 (SE 0.57) in the donepezil group (P=0.956)," Dr. Dichgans said.

On executive function tests -- TMT part A and part B, which measure the time to complete specific tasks and a 25-item interview test -- there was a significant treatment effect favoring donepezil (P=0.015 for TMT part A, P=0.023 for TMT part B, and P=0.022 for the interview test).

Seven of the placebo patients discontinued treatment because of adverse events, as did 10 of those in the donepezil group. Overall, adverse events were reported by 81% of the patients in the donepezil arm versus 71% of patients in the placebo group.

Most patients reported mild to moderate events, which were similar in both groups. Exceptions were nausea and vomiting, which were more common in the donepezil group.

There were 15 serious adverse events in the donepezil arm -- including 11 nervous system disorders and four ischemic strokes -- versus nine serious events in the placebo arm. The only death -- cardiac failure -- occurred in the placebo arm and was ruled unrelated to the study drug.

Commenting in Lancet Neurology, Lon S. Schneider, M.D., of the University of Southern California in Los Angeles, wrote that null results might be as much a factor of the sample, which included patients who had severe dementia as well as those with virtually no substantial cognitive impairment.

That mix, he wrote, suggests that "the investigators did not have the sample of patients with CADASIL that they were seeking or did not have a sample that was best suited to test the effects of donepezil."

Dr. Schneider concluded that in future trials "the sample selection should be reconsidered to define better the cognitive impairment syndrome to be treated," and better "identify the individual patients who benefit from treatment."

The study was funded by Eisai Medical Research of Ridgefield Park, N.J.

Dr. Dichgans worked as a consultant for Eisai Medical Research.

Dr. Schneider disclosed that he received honoraria from or served as a consultant to Forest Pharmaceuticals, Johnson and Johnson, Lundbeck, Merz GmB, Novartis, and Pfizer.

Dr. Gorelick said he was a consultant for NPS, Eisai, Searle/Lorex, and Roche Laboratories.

Reviewed by Zalman S. Agus, MD Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania